H11 kinase is the eukaryotic homologue of the viral protein ICP10, an activator of the Ras pathway, which is responsible for the growth and neoplastic transformation of immortalized eukaryotic cells infected by Herpes Simplex Virus Type 2 (HSV2) (Smith et al. (2000) J. Biol. Chem. 275:25690-25699). Similarly, H11 kinase overexpression has been linked to different forms of neoplasia, including melanoma (Smith et al. (2000) supra) and breast cancer (Charpentier et al. (2000) Cancer Res. 60:5977-5893). However, in normal tissues, H11 kinase is predominantly expressed in heart and skeletal muscle (Kappe et al. (2001) Biochim. Biophys. Acta. 1520:1-6; Depre et al. (2002) Circ. Res. 91:1007-1014), where its precise function remains unknown.
The upregulation of H11 kinase gene and protein expression in a model of prolonged and stable left ventricular hypertrophy in the dog heart (Depre et al. (2002) supra) suggests that H11 kinase may participate in mechanisms of cell growth. Accordingly, a cardiac-specific transgenic mouse overexpressing H11 kinase was generated, which developed myocardial hypertrophy (Depre et al. (2002) supra). In addition, it has been shown that H11 kinase expression increases in a swine model of reversible ischemia (stunning) together with a cluster of genes promoting cell survival (Depre et al. (2001) Proc. Natl. Acad. Sci. USA. 98:9336-9341). H11 kinase expression has also been shown to increase in the heart as well under conditions of long-term ischemia, referred to as myocardial hibernation (Depre, et al. (2004) Circ. Res. 95:433-44). Further, H11K activates the serine/threonine kinase Akt/PKB, which can prevent cell death through an inhibition by phosphorylation of pro-apoptotic effectors, including glycogen synthase kinase-3β (GSK-3β), caspase-9, Bad and the transcription factor forkhead (Cantley (2002) Science 296:1655-1657). H11K has also been found to promote glucose metabolism in the heart in vivo (Wang, et al. (2004) Mol Cell Biochem. 265:71-78). Increased reliance upon glucose represents a metabolic survival response to ischemia (Depre, et al. (1999) Circulation 99:578-588), which is complementary to the anti-apoptotic mechanisms of Akt. The major activator of glucose utilization in the ischemic heart is the 5′AMP-activated protein kinase (AMPK), which promotes cell survival by a switching to anaerobic glucose utilization (Russell, et al. (2004) J. Clin. Invest. 114:495-503). Although Akt and AMPK appear complementary in promoting cell survival, they have an opposite effect on cardiac cell growth through a reciprocal regulation of the mammalian target of rapamycin (Hay and Sonenberg (2004) Genes Dev. 18:1926-1945). Thus, based on these observations, H11 kinase may have cytoprotective effects, which could promote cell survival and prevent irreversible ischemic damage in stunned myocardium. In contrast, overexpression of H11 kinase in vitro in different cell types has been shown to promote apoptosis (Gober et al. (2003) J. Biol. Chem. M303834200). Therefore, the mechanism by which H11 kinase controls cardiac cell survival and death remains to be elucidated.